U.S. patent number 7,342,022 [Application Number 10/499,388] was granted by the patent office on 2008-03-11 for compounds in the treatment of dementia related diseases, alzheimer's disease and conditions associated with glycogen synthase kinase-3.
This patent grant is currently assigned to AstraZeneca AB. Invention is credited to Stefan Berg, Ratan Bhat, Philip Edwards, Sven Hellberg.
United States Patent |
7,342,022 |
Berg , et al. |
March 11, 2008 |
Compounds in the treatment of dementia related diseases,
Alzheimer's Disease and conditions associated with glycogen
synthase kinase-3
Abstract
The present invention relates to new compounds of formula I
wherein R.sup.1, R.sup.2, R.sup.3, n, m are defined as in claim 1,
a process for their preparation and new intermediates used in the
preparation thereof, pharmaceutical formulations containing said
therapeutically active compounds and to the use of said active
compounds in therapy, especially in the prevention and/or treatment
of dementia related diseases, Alzheimer's Disease and conditions
associated with glycogen synthase kinase-3 ##STR00001##
Inventors: |
Berg; Stefan (Sodertalje,
SE), Bhat; Ratan (Sodertalje, SE), Edwards;
Philip (Wilmington, DE), Hellberg; Sven (Sodertalje,
SE) |
Assignee: |
AstraZeneca AB (Sodertalje,
SE)
|
Family
ID: |
23352481 |
Appl.
No.: |
10/499,388 |
Filed: |
December 18, 2002 |
PCT
Filed: |
December 18, 2002 |
PCT No.: |
PCT/SE02/02371 |
371(c)(1),(2),(4) Date: |
June 17, 2004 |
PCT
Pub. No.: |
WO03/055877 |
PCT
Pub. Date: |
July 10, 2003 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20050222181 A1 |
Oct 6, 2005 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60344885 |
Dec 21, 2001 |
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Current U.S.
Class: |
514/266.2;
540/524; 544/284; 514/212.08 |
Current CPC
Class: |
C07D
413/14 (20130101); A61P 21/00 (20180101); C07D
403/14 (20130101); A61P 25/24 (20180101); A61P
25/18 (20180101); A61P 25/00 (20180101); A61P
3/10 (20180101); A61P 9/10 (20180101); A61P
15/00 (20180101); A61P 43/00 (20180101); A61P
25/16 (20180101); A61P 3/08 (20180101); A61P
15/16 (20180101); A61P 25/14 (20180101); A61P
25/28 (20180101); C07D 403/04 (20130101); A61P
17/14 (20180101) |
Current International
Class: |
A61K
31/55 (20060101); A61K 31/517 (20060101); C07D
403/14 (20060101); C07D 401/14 (20060101); C07D
403/04 (20060101); A61P 25/28 (20060101); A61P
3/08 (20060101); C07D 209/34 (20060101) |
Field of
Search: |
;514/266.2,217.06,217.02,212.08 ;540/567,524 ;544/284 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1136493 |
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Sep 2001 |
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EP |
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WO-95/33750 |
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Dec 1995 |
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WO |
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WO-97/42187 |
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Nov 1997 |
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WO |
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WO-99/10349 |
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Mar 1999 |
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WO |
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WO-00/10975 |
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Mar 2000 |
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WO |
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Other References
Piyasena Hewawasam et al., "Synthesis and Structure-Activity
Relationships of 3-Arylosindoles: A new Class of Calcium-Dependent,
Large Conductance Potassium (Maxi-K) Channel Openers with
Neuroprotective Properties". J. Med. Chem., vol. 45, 2002, pp.
1487-1499. cited by other .
Imahori and Uchida., Physiology and Pathology of Tau Protein
Kinases in Relation to Alzheimer'Disease. J. Biochem 121, 1997, pp.
179-188. cited by other .
Hoshi et al., "Regulation of mitochondrial pyruvate dehydrogenase
activity by tau protein kinase I/glycogen synthase kinase 3.beta.
in brain", PNAS vol. 93, Apr. 1996, pp. 2719-2723. cited by other
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Bhat et al., "Regulation and localization of tyrosine.sup.216
phosphorylation of glycogen synthase kinase-3.beta. in cellular and
animal models of neuronal degeneration", PNAS vol. 97, No. 20, Sep.
2000, pp. 11074-11079. cited by other .
Stambolic et al., "Lithium inhibits glycogen synthase kinase-3
activity and mimics wingless signalling in intact cells", Current
Biol. 1996, vol. 6, pp. 1664-1668. cited by other .
Klein and Melton, "A molecular mechanism for the effect of lithium
on development", Proc. Natl. Acad. Sci. USA, vol. 93, Aug. 1996,
pp. 8455-8459. cited by other .
Kozlovsky et al., "Low GSK-3.beta. Immunoreactivity in Postmortem
Frontal Cortex of Schizophrenic Patients", Am. J. Psychiatry, May
2000, vol. 157(5), pp. 831-833. cited by other .
Cotter et al., Abnormalities of Wnt signalling in
schizophrenia-evidence for neurodevelopmental abnormality,
NeuroReport, vol. 9, May 1998, pp. 1379-1383. cited by other .
Nikoulina et al., "Potential role of glycogen synthase kinase-3 in
skeletal muscle insulin resistance if type 2 diabetes", Diabetes,
vol. 49, Feb. 2000, pp. 263-271. cited by other .
Gat et al., "De Novo Hair Follicle Morphogenesis and Hair Tumors in
Mice Expressing a Truncated .beta.-Catenin in Skin", Cell, vol. 95,
Nov. 1998, pp. 605-614. cited by other .
Vijajaraghavan et al., "Role for Phosphorylation of Glycogen
Synthase Kinase-3.alpha. in Bovine Sperm Motility Regulation",
Biol. Reprod. vol. 62 Jan. 2000, pp. 1647-1654. cited by
other.
|
Primary Examiner: Bernhardt; Emily
Assistant Examiner: Truong; Tamthom N.
Parent Case Text
This application is a 371 of PCT/SE02/02371, filed on Dec. 18,
2002, which claims the benefit of the Provisional Application No.
60/344,885, filed on Dec. 21, 2001.
Claims
The invention claimed is:
1. A compound which is 3-[7-2(-Methoxyethoxy)
quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid
(2-oxoazepan-3-yl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid [3-(methylphenylamino)propyl]amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid [3-(1-hydroxyethyl)phenyl]amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (4-cyclohexylphenyl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (4,4-diethoxybutyl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (1H-benzoimidazol-2-ylmethyl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid [2-(5-methyl-1H-indol-3-yl)ethyl]amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid 4-sulfamoylbenzylamide or
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (1-benzylpiperidin-4-yl)amide, as a free base or a salt
thereof.
Description
FIELD OF THE INVENTION
The present invention relates to new compounds of formula I, as a
free base or salts thereof, to pharmaceutical formulations
containing said compounds and to the use of said compounds in
therapy. The present invention further relates to processes for the
preparation of compounds of formula I and to new intermediates used
in the preparation thereof.
BACKGROUND OF THE INVENTION
Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein
kinase composed of two isoforms (.alpha. and .beta.), which are
encoded by distinct genes but are highly homologous within the
catalytic domain. GSK3 is highly expressed in the central and
peripheral nervous system. GSK3 phosphorylates several substrates
including tau, .beta.-catenin, glycogen synthase, pyruvate
dehydrogenase and elongation initiation factor 2b (eEF2b). Insulin
and growth factors activate protein kinase B, which phosphorylates
GSK3 on serine 9 the residue and inactivates it.
Alzheimer's Disease (AD) Dementias, and Taupathies.
AD is characterized by cognitive decline, cholinergic dysfunction
and neuronal death, neurofibrillary tangles and senile plaques
consisting of amyloid-.beta. deposits. The sequence of these events
in AD is unclear, but believed to be related. Glycogen synthase
kinase 3.beta. (GSK3.beta.) or Tau (.tau.) phosphorylating kinase
selectively phosphorylates the microtubule associated protein .tau.
in neurons at sites that are hyperphosphorylated in AD brains.
Hyperphosphorylated protein .tau. has lower affinity for
microtubules and accumulates as paired helical filaments, which are
the main components that constitute neurofibrillary tangles and
neuropil threads in AD brains. This results in depolymerization of
microtubules, which leads to dying back of axons and neuritic
dystrophy. Neurofibrillary tangles are consistently found in
diseases such as AD, amyotrophic lateral sclerosis,
parkinsonism-dementia complex of Gaum, corticobasal degeneration,
dementia pugilistica and head trauma, Down's syndrome,
postencephalatic parkinsonism, progressive supranuclear palsy,
Niemann-Pick's Disease and Pick's Disease. Addition of
amyloid-.beta. to primary hippocampal cultures results in
hyperphosphorylation of .tau. and a paired helical filaments-like
state via induction of GSK3.beta. activity, followed by disruption
of axonal transport and neuronal death (Imahori and Uchida, J.
Biochem 121:179-188, 1997). GSK3.beta. preferentially labels
neurofibrillary tangles and has been shown to be active in
pre-tangle neurons in AD brains. GSK3 protein levels are also
increased by 50% in brain tissue from AD patients. Furthermore,
GSK3.beta. phosphorylates pyruvate dehydrogenase, a key enzyme in
the glycolytic pathway and prevents the conversion of pyruvate to
acetyl-Co-A (Hoshi et al., PNAS 93:2719-2723, 1996). Acetyl-Co-A is
critical for the synthesis of acetylcholine, a neurotransmitter
with cognitive functions. Thus, GSK3.beta. inhibition may have
beneficial effects in progression as well as the cognitive deficits
associated with Alzheimer's disease and other above-referred to
diseases.
Chronic and Acute Neurodegenerative Diseases.
Growth factor mediated activation of the PI3K/Akt pathway has been
shown to play a key role in neuronal survival. The activation of
this pathway results in GSK3.beta. inhibition. Recent studies (Bhat
et. al., PNAS 97:11074-11079 (2000)) indicate that GSK3.beta.
activity is increased in cellular and animal models of
neurodegeneration such as cerebral ischemia or after growth factor
deprivation. For example, the active site phosphorylation was
increased in neurons vulnerable to apoptosis, a type of cell death
commonly thought to occur in chronic and acute degenerative
diseases such as Alzheimer's Disease, Parkinson's Disease,
amyotrophic lateral sclerosis, Huntington's Disease and HIV
dementia, ischemic stroke and head trauma. Lithium was
neuroprotective in inhibiting apoptosis in cells and in the brain
at doses that resulted in the inhibition of GSK3.beta.. Thus
GSK3.beta. inhibitors could be useful in attenuating the course of
neurodegenerative diseases.
Bipolar Disorders (BD)
Bipolar Disorders are characterised by manic episodes and
depressive episodes. Lithium has been used to treat BD based on its
mood stabilising effects. The disadvantage of lithium is the narrow
therapeutic window and the danger of overdosing that can lead to
lithium intoxication. The recent discovery that lithium inhibits
GSK3 at therapeutic concentrations has raised the possibility that
this enzyme represents a key target of lithium's action in the
brain (Stambolic et al., Curr. Biol. 6:1664-1668, 1996; Klein and
Melton; PNAS 93:8455-8459, 1996). Inhibition of GSK3.beta. may
therefore be of therapeutic relevance in the treatment of BD as
well as in AD patients that have affective disorders.
Schizophrenia
GSK3 is involved in signal transduction cascades of multiple
cellular processes, particularly during neural development.
Kozlovsky et al (Am J Psychiatry 2000 May; 157(5):831-3) found that
GSK3.beta. levels were 41% lower in the schizophrenic patients than
in comparison subjects. This study indicates that schizophrenia
involves neurodevelopmental pathology and that abnormal GSK3
regulation could play a role in schizophrenia. Furthermore, reduced
.beta.-catenin levels have been reported in patients exhibiting
schizophrenia (Cotter et al., Neuroreport 9:1379-1383 (1998)).
Diabetes
Insulin stimulates glycogen synthesis in skeletal muscles via the
dephosphorylation and thus activation of glycogen synthase. Under
resting conditions, GSK3 phosphorylates and inactivates glycogen
synthase via dephosphorylation. GSK3 is also over-expressed in
muscles from Type II diabetic patients (Nikoulina et al., Diabetes
2000 February; 49(2):263-71). Inhibition of GSK3 increases the
activity of glycogen synthase thereby decreasing glucose levels by
its conversion to glycogen. GSK3 inhibition may therefore be of
therapeutic relevance in the treatment of Type I and Type II
diabetes and diabetic neuropathy.
Hair Loss
GSK3 phosphorylates and degrades .beta.-catenin. .beta.-catenin is
an effector of the pathway for keratonin synthesis. .beta.-catenin
stabilisation may be lead to increase hair development. Mice
expressing a stabilised .beta.-catenin by mutation of sites
phosphorylated by GSK3 undergo a process resembling de novo hair
morphogenesis (Gat et al., Cell 1998 Nov. 25;95 (5):605-14)). The
new follicles formed sebaceous glands and dermal papilla, normally
established only in embryogenesis. Thus GSK3 inhibition may offer
treatment for baldness.
Oral Contraceptives
Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54)
reported that GSK3 is high in motile versus immotile sperm.
Immunocytochemistry revealed that GSK3 is present in the flagellum
and the anterior portion of the sperm head. These data suggest that
GSK3 could be a key element underlying motility initiation in the
epididymis and regulation of mature sperm function. Inhibitors of
GSK3 could be useful as contraceptives for males.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide compounds having
a selective inhibiting effect at GSK3 as well as having a good
bioavailability.
Accordingly, the present invention provides a compound of formula
I:
##STR00002## wherein: R.sup.1 is hydrogen; R.sup.2 is carboxy,
C.sub.2-6alkoxycarbonyl, fluoromethyl, difluoromethyl,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, or a group
R.sup.4X.sup.1, wherein X.sup.1 is C.sub.2-4alkanoyl,
CONR.sup.5R.sup.6, SO.sub.2NR.sup.7R.sup.8 or SO.sub.2R.sup.9
(wherein R.sup.5 and R.sup.7 each independently are hydrogen or
C.sub.1-2alkyl and R.sup.6, R.sup.8 and R.sup.9 each independently
are C.sub.1-4alkyl or a bond and wherein R.sup.4 is linked to
R.sup.6, R.sup.8 and R.sup.9); and R.sup.4 is NR.sup.AR.sup.B,
OR.sup.A, CH(OC.sub.1-6alkyl).sub.2, or a 7 membered heterocyclic
group with one or two heteroatoms selected independently from O, S
and N, which heterocyclic group may be saturated or unsaturated and
which heterocyclic group may be substituted with one or two
substituents selected independently from hydroxy, oxo, halogeno,
C.sub.1-3alkyl, C.sub.3-6cycloalkyl, C.sub.1-3alkoxy,
C.sub.1-3alkanoyloxy, C.sub.1-3alkylOH, C.sub.1-3alkylphenyl,
carbamoyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, trifluoromethyl, cyano,
amino, nitro and C.sub.1-4alkoxycarbonyl, and said 7 membered
heterocyclic group may optionally be fused with a 5 or 6 membered
saturated or unsaturated ring containing atoms selected
independently from C, N, O or S, which may be substituted with one
or two substituents selected independently from hydroxy, oxo,
halogeno, trifluoromethyl, C.sub.1-3alkyl, C.sub.3-6cycloalkyl,
C.sub.1-3alkoxy, cyano, amino and nitro; or R.sup.4 is a phenyl or
a 5 or 6 membered heterocyclic group with one or two heteroatoms
selected independently from O, S and N, which heterocyclic group
may be saturated or unsaturated and which phenyl or heterocyclic
group may be substituted with one or two substituents selected
independently from oxo, C.sub.3-6cycloalkyl, C.sub.1-3alkylOH,
C.sub.1-3alkylphenyl, carbamoyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; or R.sup.4 is phenyl or a 5
or 6 membered heterocyclic group with one or two heteroatoms
selected independently from O, S and N, which heterocyclic group
may be saturated or unsaturated and which phenyl or heterocyclic
group may be substituted with one or two substituents selected
independently from hydroxy, oxo, halogeno, C.sub.1-3alkyl,
C.sub.3-6cycloalkyl, C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy,
C.sub.1-3alkylOH, C.sub.1-3alkylphenyl, carbamoyl,
N--C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, trifluoromethyl, cyano,
amino, nitro and C.sub.1-4alkoxycarbonyl, and said phenyl or 5 or 6
membered heterocyclic group is fused with a 5 or 6 membered
saturated or unsaturated ring containing atoms selected
independently from C, N, O or S, which may be substituted with one
or two substituents selected independently from hydroxy, oxo,
halogeno, trifluoromethyl, C.sub.1-3alkyl, C.sub.3-6cycloalky),
C.sub.1-3alkoxy, cyano, amino and nitro; and R.sup.A and R.sup.B
are selected independently from hydrogen, C.sub.1-6alkyl, phenyl
and benzyl; R.sup.3 is hydroxy, halogeno, nitro, fluoromethyl,
difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethyl, C.sub.1-3alkyl, cyano,
amino or R.sup.10X.sup.2, wherein X.sup.2 is O, CH.sub.2, S, SO,
SO.sub.2, NR.sup.11CO, CONR.sup.12, SO.sub.2NR.sup.13,
NR.sup.14SO.sub.2 or NR.sup.15 (wherein R.sup.11, R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 each independently are hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl), or X.sup.2 is a
direct bond; and R.sup.10 is selected from one of the following
groups: 1) hydrogen or C.sub.2-5alkyl which may be substituted with
one or more groups selected independently from hydroxy, fluoro and
amino; 2) C.sub.1-5alkylX.sup.3COR.sup.16 (wherein X.sup.3 is O or
NR.sup.17 (wherein R.sup.17 is hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16 is C.sub.1-3alkyl,
NR.sup.18R.sup.19 or OR.sup.20 (wherein R.sup.18, R.sup.19 and
R.sup.20 each independently are hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.4R.sup.21
(wherein X.sup.4 is O, S, SO, SO.sub.2, OCO, NR.sup.22CO,
CONR.sup.23, SO.sub.2NR .sup.24, NR.sup.25SO.sub.2 or NR.sup.26
(wherein R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 each
independently are hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.21 is hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered
saturated heterocyclic group with one or two heteroatoms selected
independently from O, S and N, which C.sub.1-3alkyl group may be
substituted with one or two substituents selected independently
from oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which
heterocyclic group may be substituted with one or two substituents
selected independently from oxo, hydroxy, halogeno, C.sub.1-4alkyl,
C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy); 4)
C.sub.1-5alkylX.sup.5C.sub.1-5alkylX.sup.6R.sup.27 (wherein X.sup.5
and X.sup.6 each independently are O, S, SO, SO.sub.2, NR.sup.28CO,
CONR.sup.29, SO.sub.2NR.sup.30, NR.sup.31SO.sub.2 or NR.sup.32
(wherein R.sup.28, R.sup.29, R.sup.30, R.sup.31 and R.sup.32 each
independently are hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.27 is hydrogen or
C.sub.1-3alkyl); 5) C.sub.1-5alkylR.sup.33 (wherein R.sup.33 is a 5
or 6 membered saturated heterocyclic group with one or two
heteroatoms selected independently from O, S and N, which
C.sub.1-5alkyl or heterocyclic group may be substituted with one or
two substituents selected independently from oxo, hydroxy,
halogeno, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.2-4alkanoyl
and C.sub.1-4alkoxy); 6) C.sub.2-5alkenylR.sup.33 (wherein R.sup.33
is as defined hereinbefore); 7) C.sub.2-5alkynylR.sup.33 (wherein
R.sup.33 is as defined hereinbefore); 8) R.sup.34 (wherein R.sup.34
is a pyridone group, a phenyl group or a 5 or 6 membered aromatic
heterocyclic group with 1 to 3 heteroatoms selected independently
from O, N and S, which pyridone, phenyl or heterocyclic group may
carry up to 5 substituents selected independently from hydroxy,
halogeno, amino, C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4hydroxyalkyl, C.sub.1-4aminoalkyl, C.sub.1-4alkylamino,
C.sub.1-4hydroxyalkoxy, carboxy, cyano, CONR.sup.35R.sup.36 and
NR.sup.37COR.sup.38 (wherein R.sup.35, R.sup.36, R.sup.37 and
R.sup.38 each independently are hydrogen, C.sub.1-4alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 9) C.sub.1-5alkylR.sup.34 (wherein
R.sup.34 is as defined hereinbefore); 10) C.sub.2-5alkenylR.sup.34
(wherein R.sup.34 is as defined hereinbefore); 11)
C.sub.2-5alkynylR.sup.34 (wherein R.sup.34 is as defined
hereinbefore); 12) C.sub.1-5alkylX.sup.7R.sup.34 (wherein X.sup.7
is O, S, SO, SO.sub.2, NR.sup.39CO, CONR.sup.40, SO.sub.2NR.sup.41
, NR.sup.42SO.sub.2 or NR.sup.43 (wherein R.sup.39, R.sup.40,
R.sup.41, R.sup.42 and R.sup.43 each independently are hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.34 is as
defined hereinbefore); 13) C.sub.2-5alkenylX.sup.8R.sup.34 (wherein
X.sup.8 is O, S, SO, SO.sub.2, NR.sup.44CO, CONR.sup.45,
SO.sub.2NR.sup.46, NR.sup.47SO.sub.2 or NR.sup.48 (wherein
R.sup.41, R.sup.45, R.sup.46, R.sup.47 and R.sup.48 each
independently are hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.34 is as defined
hereinbefore); 14) C.sub.2-5alkynylX.sup.9R.sup.34 (wherein X.sup.9
is O, S, SO, SO.sub.2, NR.sup.49CO, CONR.sup.50, SO.sub.2NR.sup.51,
NR.sup.52SO.sub.2 or NR.sup.53 (wherein R.sup.49, R.sup.50,
R.sup.51, R.sup.52 and R.sup.53 each independently are hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.34 is as
defined hereinbefore); and 15)
C.sub.1-3alkylX.sup.10C.sub.1-3alkylR.sup.34 (wherein X.sup.10 is
O, S, SO, SO.sub.2, NR.sup.54CO, ONR.sup.55, SO.sub.2NR.sup.56,
NR.sup.57SO.sub.2 or NR.sup.58 (wherein R.sup.54, R.sup.55,
R.sup.56, R.sup.57 and R.sup.58 each independently are hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.34 is as
defined hereinbefore); 16) R.sup.33 (wherein R.sup.33 is as defined
hereinbefore); and 17) C.sub.1-3alkylX.sup.10C.sub.1-3alkylR.sup.33
(wherein X.sup.10 and R.sup.33 are as defined hereinbefore)); n is
1, 2, 3 or 4; m is 1, 2, 3 or 4; as a free base or salts
thereof.
One aspect of the invention relates to compounds of formula I,
wherein R.sup.2 is carboxy, fluoromethyl, difluoromethyl,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, or a group
R.sup.4X.sup.1, wherein X.sup.1 is C.sub.2-4alkanoyl,
CONR.sup.5R.sup.6, SO.sub.2NR.sup.7R.sup.8 or SO.sub.2R.sup.9
(wherein R.sup.5 and R.sup.7 each independently are hydrogen or
C.sub.1-2alkyl and R.sup.6, R.sup.8 and R.sup.9 each independently
are C.sub.1-4alkyl or a bond and wherein R.sup.4 is linked to
R.sup.6, R.sup.8 and R.sup.9); and R.sup.4 is NR.sup.AR.sup.B,
OR.sup.A, CH(OC.sub.1-6alkyl).sub.2, or a 7 membered heterocyclic
group with one or two heteroatoms selected independently from O, S
and N, which heterocyclic group may be saturated or unsaturated and
which heterocyclic group may be substituted with one or two
substituents selected independently from hydroxy, oxo, halogeno,
C.sub.1-3alkyl, C.sub.3-6cycloalkyl, C.sub.1-3alkoxy,
C.sub.1-3alkanoyloxy, C.sub.1-3alkylOH, C.sub.1-3alkylphenyl,
carbamoyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, trifluoromethyl, cyano,
amino, nitro and C.sub.1-4alkoxycarbonyl, and said 7 membered
heterocyclic group may optionally be fused with a 5 or 6 membered
saturated or unsaturated ring containing atoms selected
independently from C, N, O or S, which may be substituted with one
or two substituents selected independently from hydroxy, oxo,
halogeno, trifluoromethyl, C.sub.1-3alkyl, C.sub.3-6cycloalkyl,
C.sub.1-3alkoxy, cyano, amino and nitro; or R.sup.4 is a phenyl or
a 5 or 6 membered heterocyclic group with one or two heteroatoms
selected independently from O, S and N, which heterocyclic group
may be saturated or unsaturated and which phenyl or heterocyclic
group may be substituted with one or two substituents selected
independently from oxo, C.sub.3-6cycloalkyl, C.sub.1-3alkylOH,
C.sub.1-3alkylphenyl, carbamoyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; or R.sup.4 is phenyl or a 5
or 6 membered heterocyclic group with one or two heteroatoms
selected independently from O, S and N, which heterocyclic group
may be saturated or unsaturated and which phenyl or heterocyclic
group may be substituted with one or two substituents selected
independently from hydroxy, oxo, halogeno, C.sub.1-3alkyl,
C.sub.3-6cycloalkyl, C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy,
C.sub.1-3alkylOH, C.sub.1-3alkylphenyl, carbamoyl,
N--C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, tri fluoromethyl, cyano,
amino, nitro and C.sub.1-4alkoxycarbonyl, and said phenyl or 5 or 6
membered heterocyclic group is fused with a 5 or 6 membered
saturated or unsaturated ring containing atoms selected
independently from C, N, O or S, which may be substituted with one
or two substituents selected independently from hydroxy, oxo,
halogeno, trifluoromethyl, C.sub.1-3alkyl, C.sub.3-6cycloalkyl,
C.sub.1-3alkoxy, cyano, amino and nitro; and R.sup.A and R.sup.B
are selected independently from hydrogen, C.sub.1-6alkyl, phenyl
and benzyl.
In another aspect of the invention R.sup.2 is carboxy or
C.sub.2-6alkoxycarbonyl.
In a third aspect of the invention X.sup.1 is CONR.sup.5R.sup.6
(wherein R.sup.5 is hydrogen or C.sub.1-2alkyl and R.sup.6 is
C.sub.1-4alkyl or a bond and wherein R.sup.4 is linked to
R.sup.6).
In yet another aspect of the invention R.sup.4 is NR.sup.AR.sup.B,
OR.sup.A, CH(OC.sub.1-6alkyl).sub.2, or a 7 membered heterocyclic
group with one or two heteroatoms selected independently from O, S
and N, which heterocyclic group may be saturated or unsaturated and
which heterocyclic group may be substituted with one or two
substituents selected independently from hydroxy, oxo, halogeno,
C.sub.1-3alkyl, C.sub.3-6cycloalkyl, C.sub.1-3alkoxy,
C.sub.1-3alkanoyloxy, C.sub.1-3alkylOH, C.sub.1-3alkylphenyl,
carbamoyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, trifluoromethyl, cyano,
amino, nitro and C.sub.1-4alkoxycarbonyl;
R.sup.A and R.sup.B are selected independently from hydrogen,
C.sub.1-6alkyl and phenyl.
In a further aspect of the R.sup.4 is phenyl or a 5 or 6 membered
heterocyclic group with one or two heteroatoms selected
independently from O and N, which heterocyclic group may be
saturated or unsaturated and which phenyl or heterocyclic group may
be substituted with one or two substituents selected independently
from oxo, C.sub.3-6cycloalkyl, C.sub.1-3alkylOH,
C.sub.1-3alkylphenyl, carbamoyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, aminosulphonyl, N--C,
alkylaminosulphonyl and N,N-di(C.sub.1-4alkyl)aminosulphonyl.
In yet another aspect of the invention R.sup.4 is phenyl or a 5 or
6 membered heterocyclic group with one or two heteroatoms selected
independently from O, S and N, which heterocyclic group may be
saturated or unsaturated, and said phenyl or 5 or 6 membered
heterocyclic group is fused with a 5 or 6 membered saturated or
unsaturated ring containing atoms selected independently from C, N,
O or S, which may be substituted with one or two substituents
selected independently from hydroxy, oxo, halogeno,
trifluoromethyl, C.sub.1-3alkyl, C.sub.3-6cycloalkyl,
C.sub.1-3alkoxy, cyano, amino and nitro.
In another aspect of the invention R.sup.3 is R.sup.10X.sup.2,
wherein X.sup.2 is O; and R.sup.10 is C.sub.1-5alkylX.sup.4R.sup.21
(wherein X.sup.4 is O or NR.sup.26 (wherein R.sup.21 and R.sup.26
independently are hydrogen, C.sub.1-3alkyl, cyclopentyl or
cyclohexyl)); and m is 1 or 2.
One aspect of the present invention relates to compounds having at
least one R.sup.2 and at least one R.sup.3 substituent, wherein
R.sup.3 represents an ester and R.sup.2 is as defined above.
The present invention further relates to compounds of general
formula I, wherein the R.sup.2 is substituted on position 5 and/or
6 and R.sup.3 is substituted on position 6, 7 and/or 8.
In a further aspect of the invention the following compounds are
provided:
3-[7-2(-Methoxyethoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-ind-
ole-5-carboxylic acid (2-oxoazepan-3-yl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid[3-(methylphenylamino)propyl]amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid [3-(1-hydroxyethyl)phenyl]amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (4-cyclohexylphenyl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (4,4-diethoxybutyl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (1H-benzoimidazol-2-ylmethyl)amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid [2-(5-methyl-1H-indol-3-yl)ethyl]amide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid 4-sulfamoylbenzylamide,
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (1-benzylpiperidin-4-yl)amide, as a free base or salts
thereof.
Listed below are definitions of various terms used in the
specification and claims to describe the present invention.
For the avoidance of doubt it is to be understood that where in
this specification a group is qualified by `hereinbefore defined`
or `defined hereinbefore` the said group encompasses the first
occurring and broadest definition as well as each and all of the
preferred definitions of that group.
For the avoidance of doubt it is to be understood that in this
specification `C.sub.1-6` means a carbon group having 1, 2, 3, 4, 5
or 6 carbon atoms.
In this specification, unless stated otherwise, the term "alkyl"
includes both straight and branched chain alkyl groups
C.sub.1-6alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl,
neo-pentyl, n-hexyl or i-hexyl.
In this specification, unless stated otherwise, the term
"C.sub.3-6cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl.
The term "alkoxy" as used herein, unless stated otherwise includes
"alkyl"O groups in which "alkyl" is as hereinbefore defined.
C.sub.1-6alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy,
n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy,
t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy.
The term "alkanoyl" as used herein, unless otherwise stated
includes formyl and alkylC.dbd.O groups in which "alkyl" is as
defined hereinbefore, for example C.sub.2alkanoyl is ethanoyl and
refers to CH.sub.3C.dbd.O, C.sub.1alkanoyl is formyl and refers to
CHO.
In this specification, unless stated otherwise, the term "alkenyl"
includes both straight and branched chain alkenyl groups but
references to individual alkenyl groups such as 2-butenyl are
specific for the straight chain version only. Unless otherwise
stated, the term "alkenyl" advantageously refers to chains with 2
to 5 carbon atoms, preferably 3 to 4 carbon atoms.
In this specification, unless stated otherwise, the term "alkynyl"
includes both straight and branched chain alkynyl groups but
references to individual alkynyl groups such as 2-butynyl are
specific for the straight chain version only. Unless otherwise
stated, the term "alkynyl" advantageously refers to chains with 2
to 5 carbon atoms, preferably 3 to 4 carbon atoms.
In this specification, unless stated otherwise, the term "bond" may
be a saturated or unsaturated bond.
In this specification, unless stated otherwise, the term "5 or 6
membered heterocyclic group with one or two heteroatoms selected
independently from O, S and N, which heterocyclic group may be
saturated or unsaturated" and "7 membered heterocyclic group with
one or two heteroatoms selected independently from O, S and N,
which heterocyclic group may be saturated or unsaturated" includes
both heteroaromatic rings and heterocyclic rings that are
saturated. Examples of such heterocyclic groups includes, but are
not limited to, furyl, isoxazolyl, isothiazolyl, oxa-azepanyl,
oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl,
pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,
imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
tetrahydropyranyl or thiomorpholinyl.
In this specification, unless stated otherwise, the term "5 or 6
membered saturated or unsaturated ring containing atoms selected
from C, N, O or S" may be, but are not limited to, furyl,
isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl,
imidazolyl, imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl,
piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,
pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl
or cyclopentyl.
In this specification, unless stated otherwise, the term "5 or 6
membered saturated heterocyclic group with one or two heteroatoms
selected independently from O, S and N" may be, but are not limited
to, imidazolidinyl, morpholinyl, piperazinyl, piperidinyl,
piperidonyl, pyrazolidinyl, pyrazolidinyl, pyrrolidinyl,
tetrahydropyranyl or thiomorpholinyl.
In this specification, unless stated otherwise, the term "5 or 6
membered aromatic heterocyclic group with 1 to 3 heteroatoms
selected independently from O, N and S" may be, but are not limited
to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl,
pyrazinyl, triazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl,
pyrrolyl, thiazolyl or thienyl.
In this specification, unless stated otherwise, the term halogeno
may be fluor, chlorine, bromine or iodine.
For the avoidance of any doubt, it is to be understood that when
X.sup.2 is, for example, a group of formula NR.sup.11CO, it is the
nitrogen atom be substituted withing the R.sup.11 group which is
attached to the quinazoline ring and the carbonyl (CO) group is
attached to R.sup.10, whereas when X.sup.2 is, for example, a group
of formula CONR.sup.12, it is the carbonyl group which is attached
to the quinazoline ring and the nitrogen atom be substituted
withing the R.sup.12 group is attached to R.sup.10. A similar
convention applies to the other two atoms X.sup.2 linking groups
such as NR.sup.14SO.sub.2 and SO.sub.2NR.sup.13. When X.sup.2 is
NR.sup.15 it is the nitrogen atom be substituted withing the
R.sup.15 group, which is linked to the quinazoline ring and to
R.sup.10. An analogous convention applies to other groups. It is
further to be understood that when X.sup.2 represents NR.sup.15 and
R.sup.15 is C.sub.1-3alkoxyC.sub.2-3alkyl it is the C.sub.2-3alkyl
moiety, which is linked to the nitrogen atom of X.sup.2 and an
analogous convention applies to other groups.
For the avoidance of any doubt, it is to be understood that in a
compound of formula I when R.sup.10 is, for example, a group of
formula C.sub.1-5alkylX.sup.10C.sub.1-5alkylR.sup.34, it is the
terminal C.sub.1-5alkyl moiety, which is linked to X.sup.10,
similarly when R.sup.10 is, for example, a group of formula
C.sub.2-5alkenylR.sup.34 it is the C.sub.2-5alkenyl moiety, which
is linked to X.sup.2 and an analogous convention applies to other
groups.
For the avoidance of any doubt, it is to be understood that when
R.sup.34 carries a C.sub.1-4aminoalkyl substituent it is the
C.sub.1-4alkyl moiety, which is attached to R.sup.34 whereas when
R.sup.34 carries a C.sub.1-4alkylamino substituent it is the amino
moiety, which is attached to R.sup.39 and an analogous convention
applies to other groups.
For the avoidance of any doubt when X.sup.1 is C.sub.2-4alkanoyl it
is the carbonyl moiety, which is linked to the heteroaromatic
oxindole group and it is the alkyl moiety, which is linked to
R.sup.4 and an analogous convention applies to other groups.
The present invention relates to the use of compounds of formula I
as hereinbefore defined as well as to the salts thereof. Salts for
use in pharmaceutical compositions will be pharmaceutically
acceptable salts, but other salts may be useful in the production
of the compounds of formula I and their pharmaceutically acceptable
salts.
Both organic and inorganic acids can be employed to form non-toxic
pharmaceutically acceptable acid addition salts of the compounds of
this invention.
A suitable pharmaceutically acceptable salt of the compounds of the
invention is, for example, an acid-addition salt, for example an
inorganic or organic acid. In addition, a suitable pharmaceutically
acceptable salt of the compounds of the invention is an alkali
metal salt, an alkaline earth metal salt or a salt with an organic
base.
Some compounds of formula I may have chiral centres and/or
geometric isomeric centres (E- and Z-isomers), and it is to be
understood that the invention encompasses all such optical,
diastereoisomers and geometric isomers.
The invention also relates to any and all tautomeric forms of the
compounds of formula I.
Methods of Preparation
Intermediates
The intermediates used in the preparation of a compound of formula
I as a free base or salts thereof, may be prepared by any process
known to be applicable to the preparation of chemically-related
compounds. Such processes include, for example, those illustrated
in PCT application WO 97/42187.
Methods of Preparation of End Products
Another object of the invention relates to processes for the
preparation of compounds of formula I, Ib and Ic.
Process A describes the preparation of compounds of formula Ib,
wherein R.sup.2 is calkoxy, comprising of,
##STR00003## hydrolysis of a compound of formula Ia, wherein
R.sup.2 is C.sub.1-6alkoxycarbonyl and R.sup.1, R.sup.3, m and n
are as defined in general formula I, to obtain the compound of
formula Ib, wherein R.sup.2 is carboxy and R.sup.1, R.sup.3, m and
n are as defined in general formula I, may be carried out under
acidic conditions using acids such as H.sub.2SO.sub.4, HCl or HBr
in a suitable solvent e.g. water, ethanol, methanol or mixtures
thereof and the reaction may occur between +20.degree. C. and
+100.degree. C. or under basic conditions using bases such as
sodium hydroxide or potassium hydroxide in a suitable solvent e.g.
water, ethanol, methanol or mixtures thereof and the reaction may
occur at a temperature between +20.degree. C. and +100.degree.
C.
Process B describes the preparation of compounds of formula Ic,
wherein R.sup.2 is R.sup.4X.sup.1, comprising of
##STR00004##
Amidation of a compound of formula Ib, wherein R.sup.2 is carboxy
and R.sup.1, R.sup.3, m and n are as defined in general formula I,
to obtain a compound of formula Ic, wherein R.sup.2 is
R.sup.4X.sup.1 and X.sup.1 is CONR.sup.5R.sup.6 and R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, m and n are as defined in
general formula I may be performed by activation of a compound of
formula Ib, wherein R.sup.2 is carboxy, by treating the compound
with coupling reagents e.g.
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and
1-hydroxybenzotriazole hydrate or hydroxybenzimidazole,
1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate,
1,1'-carbonyldiimidazole or
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate, or using an acyl halide reagent e.g. cyanuric
chloride, oxalyl chloride, thionyl chloride or
bromotrispyrrolidinophosphonium hexafluorophosphate, followed by
treatment with the appropriate amine with or without the presence
of N,N-dimethylaminopyridine, in a suitable solvent such as
N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone,
methylene chloride or chloroform at a reaction temperature between
0.degree. C. and +80.degree. C.
Alternatively, compounds of formula I, may be preparared by process
C, comprising of
##STR00005## reacting a compound of formula II, wherein L.sup.1 is
a leaving group such as SCH.sub.3 or a halogen e.g. chlorine or
bromine and R.sup.3 and m are as defined in general formula I, with
a compound of formula III, wherein R.sup.1, R.sup.2, and n are as
defined in general formula I.
Thus, the reaction of the process may be carried out in an
appropriate solvent such as an ether e.g. tetrahydrofuran or
1,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or a
dipolar aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one or
dimethylsulphoxide and the reaction is conveniently effected at a
temperature in the range of +10 to +150.degree. C., preferably in
the range of +20 to +90.degree. C. The reaction is advantageously
effected in the presence of a base. Such a base may be an organic
amine base such as pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, morpholine,
N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene,
tetramethylguanidine, an alkali metal or alkaline earth metal
carbonate or hydroxide such as sodium carbonate, potassium
carbonate, calcium carbonate, sodium hydroxide or potassium
hydroxide. Alternatively, such a base is an alkali metal hydride
such as sodium hydride, or an alkali metal or alkaline earth metal
amide such as sodium amide, sodium bis(trimethylsilyl)amide,
potassium amide or potassium bis(trimethylsilyl)amide. When it is
desired to obtain the acid salt, the free base may be treated with
an acid, using a conventional procedure.
Intermediates
The present invention further relates to new compounds and the use
of these compounds in the preparation of compounds of formula I as
defined hereinbefore.
In one aspect of the invention the compound is a compound of
formula II,
##STR00006## wherein: L.sup.1 is SCH.sub.3; R.sup.3 is
R.sup.10X.sup.2, wherein X.sup.2 is O, CH.sub.2, S, SO, SO.sub.2,
NR.sup.11CO, CONR.sup.12, SO.sub.2NR.sup.13, NR.sup.14SO.sub.2 or
NR.sup.15 (wherein R.sup.11, R.sup.12, R.sup.13, R.sup.14 and
R.sup.15 each independently are hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), or X.sup.2 is a direct bond; and
R.sup.10 is C.sub.1-5alkylX.sup.4R.sup.21 (wherein X.sup.4 is O or
NR.sup.26 (wherein R.sup.21 and R.sup.26 independently are
hydrogen, C.sub.1-3alkyl, cyclopentyl or cyclohexyl)); and m is 1
or 2.
In one aspect of the invention the compounds
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid, methyl
2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate
and compounds of formula II are used for the preparation of
compounds of formula I.
EXAMPLES
The invention will now be illustrated by the following non-limiting
Examples.
Example 1
Methyl
2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carbox-
ylate
Sodium hydride (58 mg, 1.45 mmol, 60% in oil) was washed with
petroleum ether (3.times.5 mL) and dried in vacuo. The solid was
suspended in tetrahydrofuran (3 mL) and methyl
2-oxo-5-indolinecarboxylate (140 mg, 0.73 mmol) in tetrahydrofuran
(2 mL) and N-methylpyrrolidinone (2 mL) was added. The reaction
mixture was stirred for 30 min at room temperature. A solution of
4-chloro-7-(2-methoxyethoxy)quinazoline (183 mg, 0.77 mmol,
described in WO 97/42187) in tetrahydrofuran (2 mL) and
N-methylpyrrolidinone (1 mL) was added and the reaction mixture was
stirred for 1.5 h at room temperature. The solvent was removed in
vacuo and 1 M hydrochloric acid was added. The precipitate formed
was filtered off and dried at 40.degree. C. in vacuo over night to
give 150 mg (99% yield) of the title compound as an orange solid:
MS (AP+) m/z 394.2 (M.sup.++1).
Example 2
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid
To a mixture of methyl
2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate
(5.15 g, 13.1 mmol), methanol (100 mL) and water (50 mL) was added
aqueous sodium hydroxide (92 mL, 1 M) and the reaction mixture was
stirred at 40.degree. C. over night. Methanol was removed in vacuo
and the basic aqueous layer was acidified with 1 M hydrochloric
acid and stirred for 30 min. The precipitate formed was filtered
off, washed with hydrochloric acid (50 mL, 1 M) and water
(2.times.50 mL) and dried in vacuo at 50.degree. C. over night. The
crude product was stirred in methanol at room temperature over
night. The solid was filtered off to give 4.23 g (85% yield) of the
title compound as an orange solid: MS (AP+) m/z 380.3
(M.sup.++1).
Examples 3-11
General Method A
Stock solution A was prepared by dissolving
2-hydroxy-3-[7-(2-methoxyethoxy)-quinazolin-4-yl]-1H-indole-5-carboxylic
acid (2.0 g), (3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (2.2 g) and hydroxybenzimidazole (1.54 g) in
N-methylpyrrolidinone (160 mL). Stock solution B was prepared by
dissolving N,N-dimethylaminopyridine (2.8 g) in
N-methylpyrrolidinone (40 mL).
The amidation reaction was performed by adding solution A (8 mL,
corresponding to
2-hydroxy-3-[7-(2-methoxyethoxy)-quinazolin-4-yl]-1H-indole-5-carboxylic
acid: 100 mg, 0.26 mmol, 1 eq;
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 110 mg,
0.51 mmol, 2.2 eq; hydroxybenzimidazole: 77 mg, 0.57 mmol, 2.2 eq)
to a reaction vessel containing the desired amine (0.4 mmol, 1.5
eq). Solution B (2 mL, corresponding to N,N-dimethylaminopyridine:
140 mg, 1.14 mmol, 4.4 eq) was added and the resulting solution was
stirred at room temperature over night. The solvent was removed in
vacuo to give the crude product.
Example 3
3-[7-2(-Methoxyethoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbo-
xylic acid (2-oxoazepan-3-yl)amide
The reaction was performed as described in method A using
(3S)-3-aminoazepan-2-one (50 mg, 0.40 mmol). The crude product was
triturated with acetonitrile to give 109 mg (86% yield) of the
title compound: MS (AP+) m/z 490.3 (M.sup.++1).
Example 4
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid[3-(methylphenylamino)propyl]amide
The reaction was performed as described in method A using
N-(3-aminopropyl)-N-methylaniline (0.07 mL, 0.395 mmol). The crude
product was triturated with ethyl acetate. The solid was decanted
and washed with methanol to give 35 mg (26% yield) of the title
compound: MS (AP+) m/z 526.3 (M.sup.++1).
Example 5
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid [3-(1 -hydroxyethyl)phenyl]amide hydrochloride
The reaction was performed as described in method A using
3-(1-hydroxyethyl)aniline (55 mg, 0.395 mmol). The crude product
was triturated with hydrochloric acid (1 M) to give 71 mg (55%
yield) of the title compound: MS (AP+) m/z 499.2 (M.sup.++1).
Example 6
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (1H-benzoimidazol-2-ylmethyl)amide
The reaction was performed as described in method A using
2-(aminomethyl)benzimidazole dihydrochloride (88 mg, 0.395 mmol).
The crude product was triturated with acetonitrile to give 28 mg
(21% yield) of the title compound: MS (AP+) m/z 509.3
(M.sup.++1).
Example 7
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (4-cyclohexylphenyl)amide hydrochloride
The reaction was performed as described in method A using
4-cyclohexylaniline (69 mg, 0.395 mmol). The crude product was
triturated with hydrochloric acid (1 M), to give 110 mg (79% yield)
of the title compound: MS (AP+) m/z 537.3 (M.sup.++1).
Example 8
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid [2-(5 -methyl-1H-indol-3-yl)ethyl]amide hydrochloride
The reaction was performed as described in method A using
5-methyltryptamine hydrochloride (83 mg, 0.395 mmol). The crude
product was triturated with hydrochloric acid (1 M), to give 101 mg
(73% yield) of the title compound: MS (AP+) m/z 536.2
(M.sup.++1).
Example 9
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid 4-sulfamoylbenzylamide
The reaction was performed as described in method A using
4-(aminomethyl)benzenesulfonamide hydrochloride (0.06 mL, 0.395
mmol). The crude product was triturated with methanol and the solid
was re-crystallised from hot methanol to give 72 mg (51% yield) of
the title compound: MS (AP+) m/z 548.3 (M.sup.++1).
Example 10
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (4,4-diethoxybutyl)amide
The reaction was performed as described in method A using
4,4-diethoxybutylamine (0.07 mL, 0.395 mmol). The crude product was
washed with acetone and the solid was washed with hot methanol to
give 10 mg (7.4% yield) of the title compound: MS (AP+) m/z 523.3
(M.sup.++1).
Example 11
2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic
acid (1-benzylpiperidin-4-yl)amide hydrochloride
The reaction was performed as described in method A using
benzyl-4-piperidylamine (0.08 mL, 0.395 mmol). The crude product
was triturated with acetone. The formed solid was stirred in
hydrochloric acid (1 M), filtered and dried in vacuo to give 39 mg
(27% yield) of the title compound: MS (AP+) m/z 552.4
(M.sup.++1).
Pharmaceutical Compositions
According to one aspect of the present invention there is provided
a pharmaceutical composition comprising a compound of formula I, as
a free base or salts thereof, for use in prevention and/or
treatment of dementia related diseases, Alzheimer's Disease and
conditions associated with glycogen synthase kinase-3 and other
conditions listed below.
The composition may be in a form suitable for oral administration,
for example as a tablet, pill, syrup, powder, granule or capsule,
for parenteral injection (including intravenous, subcutaneous,
intramuscular, intravascular or infusion) as a sterile solution,
suspension or emulsion, for topical administration as an ointment,
patch or cream or for rectal administration as a suppository.
In general the above compositions may be prepared in a conventional
manner using pharmaceutically carriers or diluents.
Suitable daily doses of the compounds of formula I in the treatment
of a mammal, including man, are approximately 0.01 to 250 mg/kg
bodyweight at peroral administration and about 0.001 to 250 mg/kg
bodyweight at parenteral administration. The typical daily dose of
the active ingredients varies within a wide range and will depend
on various factors such as the relevant indication, the route of
administration, the age, weight and sex of the patient and may be
determined by a physician.
Medical Use
Surprisingly, it has been found that the compounds defined in the
present invention, as a free base or salts thereof, are useful in
therapy. The compounds of the present invention are well suited for
inhibiting glycogen synthase kinase-3 (GSK3). Accordingly, the
compounds of the present invention are expected to be useful in the
prevention and/or treatment of conditions associated with glycogen
synthase kinase-3 activity, i.e. the compounds may be used to
produce an inhibitory effect of GSK3 in mammals, including man, in
need of such prevention and/or treatment.
GSK3 is highly expressed in the central and peripheral nervous
system and in other tissues. Thus, it is expected that compounds of
the invention are well suited for the prevention and/or treatment
of conditions associated with glycogen synthase kinase-3 in the
central and peripheral nervous system. In particular, the compounds
of the invention are expected to be suitable in the manufacture of
a medicament for the prevention and/or treatment of dementia
related diseases and Alzheimer's Disease.
The dementia related diseases are selected from the group
consisting of Frontotemporal dementia Parkinson's Type, Parkinson
dementia complex of Guam, HIV dementia, diseases with associated
neurofibrillar tangle pathologies, predemented states, vascular
dementia, dementia with Lewy bodies, Frontotemporal dementia and
dementia pugilistica.
The compounds of the invention are also expected to be suitable in
the manufacture of a medicament for the prevention and/or treatment
of amyotrophic lateral sclerosis, corticobasal degeneration, Down
syndrome, Huntington's Disease, Parkinson's Disease,
postencephelatic parkinsonism, progressive supranuclear palsy,
Pick's Disease, Niemann-Pick's Disease, stroke, head trauma and
other chronic neurodegenerative diseases, Bipolar Disease,
affective disorders, depression, schizophrenia, cognitive
disorders, hair loss and contraceptive medication.
The compounds of the invention are further expected to be suitable
in the manufacture of a medicament for the prevention and/or
treatment of Mild Cognitive Impairment, Age-Associated Memory
Impairment, Age-Related Cognitive Decline, Cognitive Impairement No
Dementia, mild cognitive decline, mild neurocognitive decline,
Late-Life Forgetfulness, memory impairment and cognitive impairment
and androgenetic alopecia.
The present invention relates also to the use of a compound of
formula I as defined hereinbefore, in the manufacture of a
medicament for the prevention and/or treatment of conditions
associated with glycogen synthase kinase-3.
In the context of the present specification, the term "therapy"
also includes "prevention" unless there are specific indications to
the contrary. The terms "therapeutic" and "therapeutically" should
be construed accordingly.
The invention also provides for a method of prevention and/or
treatment of dementia related diseases, Alzheimer's Disease and
conditions associated with glycogen synthase kinase-3 and other
conditions listed above comprising administrering to a mammal,
including man, in need of such prevention and/or treatment a
therapeutically effective amount of a compound of formula I, as
hereinbefore defined.
Non-Medical Use
In addition to their use in therapeutic medicine, the compounds of
formula I as a free base or salts thereof, are also useful as
pharmacological tools in the development and standardisation of in
vitro and in vivo test systems for the evaluation of the effects of
inhibitors of GSK3 related activity in laboratory animals such as
cats, dogs, rabbits, monkeys, rats and mice, as part of the search
for new therapeutics agents.
Pharmacology
Determination of ATP Competition in Scintillation Proximity
GSK3.beta. Assay.
GSK3.beta. Scintillation Proximity Assay.
The competition experiments were carried out in duplicate with 10
different concentrations of the inhibitors in clear-bottom
microtiter plates (Wallac, Finland). A biotinylated peptide
substrate,
Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO.sub.3H.sub.2)-Pro-G-
ln-Leu (AstraZeneca, Lund), was added at a final concentration of 1
.mu.M in an assay buffer containing 1 mU recombinant human
GSK3.beta. (Dundee University, UK), 12 mM morpholinepropanesulfonic
acid (MOPS), pH 7.0, 0.3 mM EDTA, 0.01% .beta.-mercaptorethanol,
0.004% Brij 35 (a natural detergent), 0.5% glycerol and 0.5 .mu. g
BSA/25 .mu.l. The reaction was initiated by the addition of 0.04
.mu.Ci [.gamma.-.sup.33P]ATP (Amersham, UK) and unlabelled ATP at a
final concentration of 1 .mu.M and assay volume of 25 .mu.l. After
incubation for 20 minutes at room temperature, each reaction was
terminated by the addition of 25 .mu.l stop solution containing 5
mM EDTA, 50 .mu.M ATP, 0.1% Triton X-100 and 0.25 mg streptavidin
coated Scintillation Proximity Assay (SPA) beads (Amersham, UK).
After 6 hours the radioactivity was determined in a liquid
scintillation counter (1450 MicroBeta Trilux, Wallac). The
inhibition curves were analysed by non-linear regression using
GraphPad Prism, USA. The K.sub.m value of ATP for GSK30, used to
calculate the inhibition constants (K.sub.i) of the various
compounds, was 20 .mu.M.
The following abbreviations have been used: ATP Adenosine
Triphophatase BSA Bovin Serum Albumin EDTA
Ethylenediaminetetraacetic acid GSK3 Glycogen synthase kinase 3
MOPS Morpholinepropanesulfonic acid SPA Scintillation Proximity
Assay Results
Typical K.sub.i values for the compounds of the present invention
are in the range of about 0.001 to about 10,000 nM. Other values
for K.sub.i are in the range of about 0.001 to about 1000 nM.
Further values for K.sub.i are in the range of about 0.001 nM to
about 300 nM.
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